Prior to the present invention it was generally believed that serine protease inhibitors could be used only to supplement a deficiency occurring as a result of a genetic defect or a chemically produced deficiency resulting from an event such as smoking. Moreover, no consideration was previously given for directly controlling diseases in which mast cells are implicated by administering serine protease inhibitors when serum levels of proteases or protease inhibitors are normal. Mast cells have been found to be implicated in diseases and events such as allergic and non-allergic rhinitis, nasal polyposis, atopic dermatitis, psoriasis, contact dermatitis, pancreatitis, emphysema, asthma, colitis, Crohn's Disease, wound healing, cluster headaches, coronary artery spasm, rheumatoid arthritis etc.
Inflammation is a non-specific response of tissues to diverse stimuli or insults and results in release of a variety of materials at the site of inflammation that induces pain. It is now recognized that mast cells are implicated in the pathophysiology of inflammatory skin conditions as well as in other physiological disorders. Mast cells provide the greatest source of histamines in acute inflammation.
Neutrophils are a source of serine elastase and cathepsin G which are important in the tissue damage of inflammation, especially in cystic fibrosis.
The most direct approach to therapy of inflammatory conditions appears to be a direct attack at the site of inflammation of the mediators of inflammation and pain and the reduction of those neutrophilic derivatives which can cause damage to existing tissue and to the growth of new tissue.
Alpha 1-antichymotrypsin is a plasma protease inhibitor synthesized in the liver. It is a single glycopeptide chain of approximately 68,000 daltons and belongs to a class of serine protease inhibitors with an apparent affinity toward chymotrypsin-like enzymes.
Alpha 2-macroglobulin is a glycoprotein containing 8-11% carbohydrate which can be isolated from plasma by gel filtration chromatography.
Alpha 1-proteinase inhibitor (alpha 1-antitrypsin) is a glycoprotein having a molecular weight of 53,000 determined by sedimentation equilibrium centrifugation. The glycoprotein consists of a single polypeptide chain to which several oligosaccharide units are covalently bonded. Human alpha 1-proteinase inhibitor has a role in controlling tissue destruction by endogenous serine proteinases. A genetic deficiency of alpha-1-proteinase inhibitor, which accounts for 90% of the trypsin inhibitory capacity in blood plasma, has been shown to be associated with the premature development of pulmonary emphysema. The degradation of elastin associated with emphysema probably results from a local imbalance of elastolytic enzymes and the naturally occurring tissue and plasma proteinase inhibitors. Alpha-1-proteinase inhibitor inhibits human pancreatic and leukocyte elastases. See Pannell et al, Biochemistry. 13, 5339 (1974); Johnson et al, Biochem. Biophys. Res. Commun., 72 33 (1976); Del Mar et al, Biochem. Biophys. Res. Commun., 88, 346 (1979); and Heimburger et al, Proc. Int. Res. Conf. Proteinase Inhibitors. 1st, 1-21 (1970).
C-reactive protein (CRP) has been reported by Mold et al in J. Exp. Med. 154, 1,703-1,708, 1,984, of protecting mice exposed to S. pneumonia.
The article of Groutas entitled "Inhibitors of Leukocyte Elastase and Leukocyte Cathepsin G Agents for the Treatment of Emphysema and Related Ailments" medical Research Reviews, Vol. 7, No. 7, 227-241 (1987), discloses the role of eglin, elastinal 1 and elastin in emphysema.
McElvaney et al in Lancet, Vol. 337, p. 337, p. 392-394, Feb. 16, 1991, which is incorporated herein by references, discloses aerosol .alpha.1-antitrypsin treatment for cystic fibrosis.
U.S. Pat. No. 4,732,973 to Barr et al discloses typical analogs of serine protease inhibitors which may be used in the present invention.
U.S. Patent No. 4,916,117 to Lezdey et al discloses the treatment of pulmonary inflammation with microcrystalline alpha-1-antichymotrypsin.
It is understood that the term "serine protease inhibitors" as used herein refers to the inhibitors derived from a particular species and inhibits the proteases of the same species. However, human serine protease inhibitors may be used in veterinary products but not visa versa.